Estrogen agonists/antagonists

ABSTRACT

Compounds of this formula                    
     are useful for treating or preventing, obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease and prostatic disease.

This application is a continuation of U.S. Ser. No. 08/849,726, filedJun. 30, 1997 now U.S. Pat. No. 6,204,286 which is the national phase ofInternational application PCT/IB95/00286, filed Apr. 24, 1995 which is acontinuation of U.S. Ser. No. 08/369,954 filed Jan. 9, 1995, now U.S.Pat. No. 5,552,412.

This invention relates to estrogen agonists and antagonists and theirpharmaceutical uses.

BACKGROUND OF THE INVENTION

The value of naturally occurring estrogens and synthetic compositionsdemonstrating “estrogenic” activity has been in their medical andtherapeutic uses. A traditional listing of the therapeutic applicationsfor estrogens alone or in combination with other active agents includes:oral contraception; relief for the symptoms of menopause; prevention ofthreatened or habitual abortion; relief of dysmenorrhea; relief ofdysfunctional uterine bleeding; an aid in ovarian development; treatmentof acne; diminution of excessive growth of body hair in women(hirsutism); the prevention of cardiovascular disease; treatment ofosteoporosis; treatment of prostatic carcinoma; and suppression ofpostpartum lactation [Goodman and Gilman, The Pharmacological Basis OfTherapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages1421-1423]. Accordingly, there has been increasing interest in findingnewly synthesized compositions and new uses for previously knowncompounds which are demonstrably estrogenic, this is, able to mimic theaction of estrogen in estrogen responsive tissue.

From the viewpoint of pharmacologists interested in developing new drugsuseful for the treatment of human diseases and specific pathologicalconditions, it is most important to procure compounds with somedemonstrable estrogen-like function but which are devoid ofproliferative side-effects. Exemplifying this latter view, osteoporosis,a disease in which bone becomes increasingly more fragile, is greatlyameliorated by the use of fully active estrogens; however, due to therecognized increased risk of uterine cancer in patients chronicallytreated with active estrogens, it is not clinically advisable to treatosteoporosis in intact women with fully active estrogens for prolongedperiods. Accordingly estrogen agonists are the primary interest andfocus.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more that 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. These cost the nation over $10billion. Hip fractures are the most serious, with 5-20% of patientsdying within one year, and over 50% of survivors being incapacitated.

The elderly are at greatest risk of osteoporosis, and the problem istherefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecast to increasethree-fold over the next 60 years, and one study estimates that therewill be 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake.

Estrogen is the agent of choice in preventing osteoporosis or postmenopausal bone loss in women; it is the only treatment whichunequivocally reduces fractures. However, estrogen stimulates the uterusand is associated with an increased risk of endometrial cancer. Althoughthe risk of endometrial cancer is thought to be reduced by a concurrentuse of a progestogen, there is still concern about possible increasedrisk of breast cancer with the use of estrogen.

Black, et al. in EP 0605193A1 report that estrogen, particularly whentaken orally, lowers plasma levels of LDL and raises those of thebeneficial high density lipoproteins (HDL's). Long-term estrogentherapy, however, has been implicated in a variety of disorders,including an increase in the risk of uterine cancer and possibly breastcancer, causing many women to avoid this treatment. Recently suggestedtherapeutic regimens, which seek to lessen the cancer risk, such asadministering combinations of progestogen and estrogen, cause thepatient to experience unacceptable bleeding. Furthermore, combiningprogesterone with estrogen seems to blunt the serum cholesterol loweringeffects of estrogen. The significant undesirable effects associated withestrogen therapy support the need to develop alternative therapies forhypercholesterolemia that have the desirable effect on serum LDL but donot cause undesirable effects.

There is a need for improved estrogen agonists which exert selectiveeffects on different tissues in the body. Tamoxifen,1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is anantiestrogen which has a palliative effect on breast cancer, but isreported to have estrogenic activity in the uterus. Gill-Sharma, et al.,J. Reproduction and Fertility (1993) 99, 395, disclose that tamoxifen at200 and 400 mg/kg/day reduces the weights of the testes and secondarysex organs in male rats.

Recently it has been reported (Osteoporosis Conference Scrip No. 1812/13Apr. 16/20, 1993, p. 29) that raloxifene,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]benzo[b] thiophene, mimics the favorable action of estrogen on bone andlipids but, unlike estrogen, has minimal uterine stimulatory effect.(Breast Cancer Res. Treat. 10(1). 1987 p 31-36 Jordan, V. C. et al.).

Neubauer, et al., The Prostate 23:245 (1993) teach that raloxifenetreatment of male rats produced regression of the ventral prostate.

Raloxifene and related compounds are described as antiestrogen andantiandrogenic materials which are effective in the treatment of certainmammary and prostate cancers. See U.S. Pat. No. 4,418,068 and Charles D.Jones, et al., J. Med. Chem. 1984, 27, 1057-1066.

Jones, et al in U.S. Pat. No. 4,133,814 describe derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxides which are useful asantifertility agents as well as suppressing the growth of mammarytumors.

Lednicer, et al., J. Med. Chem., 12, 881 (1969) described estrogenantagonists of the structure

wherein R² is phenyl or cyclopentyl and R³ is H,

or —CH₂CHOHCH₂OH.

Bencze, et al., J. Med. Chem., 10, 138 (1967) prepared a series oftetrahydronaphthalenes intended to achieve separation of estrogenic,antifertility and hypocholesterolemic activities. These structures arethe general formula

wherein R¹ is H or OCH₃; R² is H, OH, OCH₃, OPO(OC₂H₅)₂,OCH₂CH₂N(C₂H₅)₂, OCH₂COOH or OCH(CH₃) COOH.

U.S. Pat. No. 3,234,090 refers to compounds which have estrogenic andantifungal properties of the formula

in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclicaryl group substituted by tertiary amino-lower alkyl-oxy, in whichtertiary amino is separated from oxy by at least two carbon atoms, R ishydrogen, an aliphatic radical, a carbocyclic aryl radical, acarbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or aheterocyclic aryl aliphatic radical, the group of the formula—(C_(n)H_(2n-2))— stands for an unbranched alkylene radical having fromthree to five carbon atoms and carrying the groups Ar and R, salts,N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, aswell as procedure for the preparation of such compounds.

U.S. Pat. No. 3,277,106 refers to basic ethers with estrogenic,hypocholesterolemic and antifertility effects which are of the formula

in which Ph is a 1,2-phenylene radical, Ar is a monocyclic aryl radicalsubstituted by at least one amino-lower alkyl-oxy group in which thenitrogen atom is separated from the oxygen atom by at least two carbonatoms, R is an aryl radical, and the portion —(C_(n)H_(2n-2))— standsfor lower alkylene forming with Ph a six- or seven-membered ring, two ofthe ring carbon atoms thereof carry the groups Ar and R, salts,N-oxides, salts of N-oxides and quaternary ammonium compounds thereof.

Lednicer, et al., in J. Med. Chem. 10, 78 (1967) and in U.S. Pat. No.3,274,213 refer to compounds of the formula

wherein R₁ and R₂ are selected from the class consisting of lower alkyland lower alkyl linked together to form a 5 to 7 ring member saturatedheterocyclic radical.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula

wherein:

A is selected from CH₂ and NR;

B, D and E are independently selected from CH and N;

Y is

(a) phenyl, optionally substituted with 1-3 substituents independentlyselected from R⁴;

(b) naphthyl, optionally substituted with 1-3 substituents independentlyselected from R⁴;

(c) C₃-C₈ cycloalkyl, optionally substituted with 1-2 substituentsindependently selected from R⁴;

(d) C₃-C₈ cycloalkenyl, optionally substituted with 1-2 substituentsindependently selected from R⁴;

(e) a five membered heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NR²— and —S(O)_(n)—,optionally substituted with 1-3 substituents independently selected fromR⁴;

(f) a six membered heterocycle containing up to two heteroatoms selectedfrom the group consisting of —O—, —NR²— and —S(O)_(n)— optionallysubstituted with 1-3 substituents independently selected from R⁴; or

(g) a bicyclic ring system consisting of a five or six memberedheterocyclic ring fused to a phenyl ring, said heterocyclic ringcontaining up to two heteroatoms selected from the group consisting of—O—, —NR²— and —S(O)_(n)—, optionally substituted with 1-3 substituentsindependently selected from R⁴;

Z¹ is

(a) —(CH₂)_(p) W(CH₂)_(q)—;

(b) —O(CH₂)_(p) CR⁵R⁶—;

(c) —O(CH₂)_(p) W(CH₂)_(q);

(d) —OCHR²CHR³—; or

(e) —SCHR²CHR³—;

G is

(a) —NR⁷R⁸;

(b)

wherein n is 0, 1 or 2; m is 1, 2 or 3; Z² is —NH—, —O—, —S—, or —CH₂—;optionally fused on adjacent carbon atoms with one or two phenyl ringsand, optionally independently substituted on carbon with one to threesubstituents and, optionally, independently on nitrogen with achemically suitable substituent selected from R⁴; or

(c) a bicyclic amine containing five to twelve carbon atoms, eitherbridged or fused and optionally substituted with 1-3 substituentsindependently selected from R⁴; or

Z¹ and G in combination may be

W is

(a) —CH₂—;

(b) —CH═CH—;

(c) —O—;

(d) —NR²—;

(e) —S(O)_(n)—;

(f)

(g) —CR²(OH)—;

(h) —CONR²—;

(i) —NR²CO—;

(j)

(k) —C≡C—;

R is hydrogen or C₁-C₆ alkyl;

R² and R³ are independently

(a) hydrogen; or

(b) C₁-C₄ alkyl;

R⁴ is

(a) hydrogen;

(b) halogen;

(c) C₁-C₆ alkyl;

(d) C₁-C₄ alkoxy;

(e) C₁-C₄ acyloxy;

(f) C₁-C₄ alkylthio;

(g) C₁-C₄ alkylsulfinyl;

(h) C₁-C₄ alkylsulfonyl;

(i) hydroxy (C₁-C₄)alkyl;

(j) aryl (C₁-C₄)alkyl;

(k) —CO₂H;

(l) —CN;

(m) —CONHOR;

(n) —SO₂NHR;

(o) —NH₂;

(p) C₁-C₄ alkylamino;

(q) C₁-C₄ dialkylamino;

(r) —NHSO₂R;

(s) —NO₂;

(t) —aryl; or

(u) —OH.

R⁵ and R⁶ are independently C₁-C₈ alkyl or together form a C3-C10carbocyclic ring;

R⁷ and R⁸ are independently

(a) phenyl;

(b) a C₃-C₁₀ carbocyclic ring, saturated or unsaturated;

(c) a C₃-C₁₀ heterocyclic ring containing up to two heteroatoms,selected from —O—, —N— and —S—;

(d) H;

(e) C₁-C₆ alkyl; or

(f) form a 3 to 8 membered nitrogen containing ring with R⁵ or R⁶;

R⁷ and R⁸ in either linear or ring form may optionally be substitutedwith up to three substituents independently selected from C₁-C₆ alkyl,halogen, alkoxy, hydroxy and carboxy;

a ring formed by R⁷ and R⁸ may be optionally fused to a phenyl ring;

e is 0, 1 or 2;

m is 1, 2 or 3;

n is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

and optical and geometric isomers thereof; and nontoxicpharmacologically acceptable acid addition salts, N-oxides, andquaternary ammonium salts thereof.

Preferred compounds of the invention are of the formula:

wherein G is

R⁴ is H, OH, F, or Cl; and B and E are independently selected from CHand N.

Especially preferred compunds are:

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;

(—)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;

Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;and

1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

In another aspect this invention provides methods of treating orpreventing a condition selected from breast cancer, osteoporosis,endometriosis and cardiovascular disease and hypercholesterolemia inmale or female mammals and benign prostatic hypertrophy and prostaticcarcinomas in male mammals which comprises administering to said mammalan amount of a compound of formula I and preferably a preferred compoundof formula I compounds as described above which is effective in treatingor preventing said condition.

In another aspect this invention provides a method of treating orpreventing obesity in mammals which comprises administering to saidmammal an amount of a compound of formula I and preferably a preferredcompound of formula I as described above which is effective in treatingor preventing obesity.

In yet another aspect this invention provides a pharmaceuticalcomposition for treating or preventing breast cancer, osteoporosis,obesity, cardiovascular disease, hypercholesterolemia, endometriosis andprostatic disease comprising a compound of formula I and apharmaceutically acceptable carrier.

In another aspect, this invention provides intermediate compounds usefulin preparing compounds of formula I. These are1-{2-[4-(6-Methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidineand1-{2-[4-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine.

DETAILED DESCRIPTION OF THE INVENTION

The terms C₁-C₃ chloroalkyl and C₁-C₃ fluoroalkyl include methyl, ethyl,propyl and isopropyl substituted to any desired degree with chlorine orfluorine atoms, from one atom to full substitution. The term C₅-C₇cycloalkyl includes cyclopentyl, cyclohexyl and cycloheptyl.

Halo means chloro, bromo, iodo and fluoro. Aryl (Ar) includes phenyl andnaphthyl optionally substituted with one to three substituentsindependently selected from R⁴ as defined above. DTT meansdithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetra acetic acid.

Estrogen agonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, andmimicking the actions of estrogen in one or more tissues.

Estrogen antagonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, and blockingthe actions of estrogen in one or more tissues.

One of ordinary skill will recognize that certain substituents listed inthis invention will be chemically incompatible with one another or withthe heteroatoms in the compounds, and will avoid these incompatibilitiesin selecting compounds of this invention. Likewise certain functionalgroups may require protecting groups during synthetic procedures whichthe chemist of ordinary skill will recognize.

The chemist of ordinary skill will recognize that certain compounds ofthis invention will contain atoms which may be in a particular opticalor geometric configuration. All such isomers are included in thisinvention; exemplary levorotatory isomers in the cis configuration arepreferred. Likewise, the chemist will recognize that variouspharmaceutically acceptable esters and salts may be prepared fromcertain compounds of this invention. All of such esters and salts areincluded in this invention.

As used in this application, prostatic disease means benign prostatichyperplasia or prostatic carcinoma.

The remedies for the prostatic diseases, breast cancer, obesity,cardiovascular disease, hypercholesterolemia and osteoporosis of thisinvention comprise, as active ingredient, a compound of formula I or asalt or ester thereof. The pharmaceutically acceptable salts of thecompounds of formula I are salts of non-toxic type commonly used, suchas salts with organic acids (e.g., formic, acetic, trifluoroacetic,citric, maleic, tartaric, methanesulfonic, benzenesulfonic ortoluenesulfonic acids), inorganic acids (e.g. hydrochloric, hydrobromic,sulfuric or phosphoric acids), and amino acids (e.g., aspartic orglutamic acids). These salts may be prepared by the methods known tochemists of ordinary skill.

The remedies for prostatic diseases, breast cancer, obesity,cardiovascular disease, hypercholesterolemia and osteoporosis of thisinvention may be administered to animals including humans orally orparenterally in the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups.

The remedies for prostatic diseases, breast cancer, obesity,cardiovascular disease, hypercholesterolemia and osteoporosis of thisinvention can be prepared by the methods commonly employed usingconventional, organic or inorganic additives, such as an excipient(e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose,talc, calcium phosphate or calcium carbonate), a binder (e.g.,cellulose, methylcellulose, hydroxymethylcellulose,polypropylpyrrolidone, polyvinylprrolidone, gelatin, gum arabic,polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch,carboxymethylcellulose, hydroxypropylstarch, low substitutedhydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calciumcitrate), a lubricant (e.g., magnesium stearate, light anhydrous silicicacid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citricacid, menthol, glycine or orange powder), a preservative (e.g., sodiumbenzoate, sodium bisulfite, methylparaben or propylparaben), astabilizer (e.g., citric acid, sodium citrate or acetic acid), asuspending agent (e.g., methylcellulose, polyvinylpyrrolidone oraluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theamount of the active ingredient in the medical composition may be at alevel that will exercise the desired therapeutical effect; for example,about 0.1 mg to 50 mg in unit dosage for both oral and parenteraladministration.

The active ingredient may be usually administered once to four times aday with a unit dosage of 0.1 mg to 50 mg in human patients, but theabove dosage may be properly varied depending on the age, body weightand medical condition of the patient and the type of administration. Apreferred dose is 0.25 mg to 25 mg in human patients. One dose per dayis preferred.

Compounds of this invention are readily prepared by the reactionsillustrated in the schemes below.

Certain compounds of formula I are conveniently prepared from anunsaturated intermediate

by hydrogenation with a noble metal catalyst in a reaction inertsolvent. Pressure and temperatures are not critical and hydrogenation isnormally accomplished in a few hours at room temperatures at 20-80 psihydrogen pressure.

The hydrogenated product is isolated, purified if desired, and the ethergroup is cleaved with an acidic catalyst in a reaction inert solvent ata temperature between 0° C. to 100° C. depending on the acidic catalystused . Hydrogen bromide at elevated temperatures, boron tribromide andaluminum chloride at 0° C. to ambient temperature have been found to beeffective for this reaction.

The product, Formula I is isolated and purified by standard procedures.

Intermediates of Formula II where A is CH₂, and B, D and E are CH aredescribed in U.S. Pat. No. 3,274,213; J. Med. Chem 10, 78 (1967); J.Med. Chem 10, 138 (1967); and J. Med. Chem. 12, 881 (1969), thedisclosures of which are herein incorporated by reference. They can alsobe prepared by procedures described below.

The preparation of the compounds of Formula I where e=1, A=CH₂,Z¹=OCH₂CH₂, G= cycloalkylamine, B=CH is shown in Scheme 1. Compounds1-2, where D and E are CH are made by alkylation of 4-bromophenol withthe corresponding N-chloroethylamine using potassium carbonate as basein a polar aprotic solvent like dimethylformamide at elevatedtemperatures. A preferred temperature is 100° C. Compounds 1-2 where Dor E or both are N are synthesized using a nucleophilic displacementreaction performed on dibromides (1-1) using hydroxy ethylcycloalkylamines under phase transfer conditions to afford bromo amines(1-2). Synthesis, 77, 573 (1980). Following halogen metal exchange usingn-butyllithium or magnesium metal, bromo amines (1-2) yield thecorresponding lithium or magnesium reagents which are allowed to reactat low temperature in the presence of cesium chloride preferably(without cesium chloride the reaction also proceeds) with6-methoxy-1-tetralone to afford either carbinols (1-3) or styrenes (1-4)after acidic workup. Treatment of either carbinols (1-3) or styrenes(1-4) with a brominating agent such as pyridinium bromide perbromideaffords bromo styrenes (1-5). Aryl or heteroaryl zinc chlorides or arylor heteroaryl boronic acids react with bromides (1-5) in the presence ofa palladium metal catalyst like tetrakis triphenyl phosphine palladium(0) to yield diaryl styrenes (1-6). [Pure & Applied Chem. 63, 419,(1991)and Bull. Chem. Soc. Jpn. 61, 3008-3010, (1988)] To prepare thepreferred compounds the substituted phenyl zinc chlorides or substitutedphenylboronic acids are used in this reaction. The aryl zinc chloridesare prepared by quench of the corresponding lithium reagent withanhydrous zinc chloride. The aryl boronic acids, that are notcommercially available, are prepared by quenching the corresponding aryllithium reagent with trialkyl borate, preferably the trimethyl ortriisopropyl borate, followed by aqueous acid workup. Acta Chemica Scan.47, 221-230 (1993). The lithium reagents that are not commerciallyavailable are prepared by halogen metal exchange of the correspondingbromide or halide with n-butyl or t-butyllithium. Alternately, thelithium reagent is prepared by heteroatom facilitated lithiations asdescribed in Organic Reactions, Volume 27, Chapter 1. Catalytichydrogenation of 1-6 in the presence of palladium hydroxide on charcoal,for example, affords the corresponding dihydro methoxy intermediateswhich were subsequently demethylated using boron tribromide at 0° C. inmethylene chloride or 48% hydrogen bromide in acetic acid at 80-100° C.to afford target structures (1-7). These compounds are racemic and canbe resolved into the enantiomers via high pressure liquid chromatographyusing a column with a chiral stationary phase like the Chiralcel ODcolumns. Alternately optical resolution can be carried out byrecrystallization of the diastereomeric salts formed with optically pureacids like 1,1′-binapthyl-2,2′-diyl hydrogen phosphate (see Example 8).

The cis compounds (1-7) can be isomerized to the trans compounds ontreatment with base (see Example 2).

When D and/or E is nitrogen the intermediates (Formula II) and compoundsof Formula I may be prepared from the corresponding dihalopyridines orpyrimidines as illustrated in Scheme 1 and as fully described for6-phenyl-5-[6-(2-pyrrolidin-1-yl-ethoxy)pyridin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-ol in Example 6.

The methyl ether of the compound of Formula I where e=1, A=CH₂,Z¹=OCH₂CH₂, G=pyrrolidine, D,E, B=CH, Y=Ph can also be convenientlyprepared by a first step of hydrogenation of nafoxidine (Upjohn & Co.,700 Portage Road, Kalamazoo, Mich. 49001) in a reaction inert solvent inthe presence of a nobel metal catalyst. Pressure and temperature are notcritical; the reaction is conveniently run in ethanol at roomtemperature for approximately 20 hours at 50 psi.

The second step is cleavage of the methoxy group which is accomplishedconveniently at room temperature with an acidic catalyst such as borontribromide in a reaction inert solvent or at 80-100° C. with hydrogenbromide in acetic acid. The product is then isolated by conventionalmethods and converted to an acid salt if desired.

Compounds of formula I wherein B is nitrogen are prepared by theprocedures illustrated in Scheme 2 and 3 and Examples 3-5 and 10-12.

The synthesis of compounds of Formula I where B=N is shown in Scheme 2.Aryl acid chlorides (2-1) on treatment with primary amines afford arylsecondary amides (2-2), which are reduced with lithium aluminum hydridein ethereal solvents to yield secondary amines (2-3). Subsequentacylation of (2-3) with aroyl acid chlorides leads to tertiary amides(2-4), which are cyclized in hot phosphorus oxychloride to yield dihydroisoquinolinium salts (2-5). Reduction with sodium borohydride toalkoxytetrahydro isoquinolines; followed by boron tribromidedemethylation in methylene chloride affords the target structures.

The synthesis of the compounds of Formula I where B=N is also describedbelow in Scheme 3. Secondary amines (3-1) on acylation withbenzyloxyaroyl chlorides (3-2) afford tertiary amides (3-3) which oncyclization with hot phosphorous oxychloride yield dihydro isoquinolinesalts (3-4). Sodium borohydride reduction of (3-4) followed bydebenzylation with aqueous hydrochloric acid affords isoquinolines(3-5), which are alkylated with the appropriately functionalizedchlorides and demethylated with boron tribromide to yield the desiredtarget structures.

The compounds of this invention are valuable estrogen agonists andpharmaceutical agents or intermediates thereto. Those which are estrogenagonists are useful for oral contraception; relief for the symptoms ofmenopause; prevention of threatened or habitual abortion; relief ofdysmenorrhea; relief of dysfunctional uterine bleeding; relief ofendometriosis; an aid in ovarian development; treatment of acne;diminution of excessive growth of body hair in women (hirsutism); theprevention and treatment of cardiovascular disease; prevention andtreatment of atherosclerosis; prevention and treatment of osteoporosis;treatment of benign prostatic hyperplasia and prostatic carcinomaobesity; and suppression of post-partum lactation. These agents alsohave a beneficial effect on plasma lipid levels and as such are usefulin treating and preventing hypercholesterolemia.

While the compounds of this invention are estrogen agonists in bone,they are also antiestrogens in breast tissue and as such would be usefulin the treatment and prevention of breast cancer.

Control and Prevention of Endometriosis

The protocol for surgically inducing endometriosis is identical to thatdescribed by Jones, Acta Endoerinol (Copenh) 106:282-8. Adult CharlesRiver Sprague-Dawley CD® female rats (200-240 g) are used. An obliqueventral incision is made through the skin and musculature of the bodywall. A segment of the right uterine horn is excised, the myometrium isseparated from the endometrium, and the segment is cut longitudinally. A5×5 mm section of the endometrium, with the epithelial lining apposed tothe body wall, is sutured at its four corners to the muscle usingpolyester braid (Ethiflex, 7-0®). The criterion of a viable graft is theaccumulation of fluid similar to that which occurs in the uterus as aresult of oestrogen stimulation.

Three weeks after transplantation of the endometrial tissue (+3 weeks)the animals are laparotomized, the volume of the explant (length x widthx height) in mm was measured with calipers, and treatment is begun. Theanimals are injected sc for 3 weeks with 10 to 1000 μg/kg/day of acompound of Formula I. Animals bearing endometrial explants are injectedsc with 0.1 ml/day of corn oil for 3 weeks served as controls. At theend of 3 week treatment period (+6 weeks), the animals are laparotomizedand the volume of the explant determined. Eight weeks after cessation oftreatment (+14 weeks) the animals are sacrificed; the explant aremeasured again. Statistical analysis of the explant volume is by ananalysis of variance.

Effect on Prostate Weight

Male Sprague-Dawley rats, three months of age are administered bysubcutaneous injection either vehicle (10% ethanol in water), estradiol(30 μg/kg), testosterone (1 mg/kg) or a compound of formula I daily for14 days (n=6/group). After 14 days the animals are sacrificed, theprostate is removed and the wet prostate weight is determined. Meanweight is determined and statistical significance (p<0.05) is determinedcompared to the vehicle-treated group using Student's t-test.

The compounds of formula I significantly (P<0.05) decrease prostateweight compared to vehicle. Testosterone has no effect while estrogen at30 μg/kg significantly reduces prostate weight.

Bone Mineral Density

Bone mineral density, a measure of bone mineral content, accounts forgreater than 80% of a bone's strength. Loss of bone mineral density withage and/or disease reduces a bone's strength and renders it more proneto fracture. Bone mineral content is accurately measured in people andanimals by dual x-ray absorptiometry (DEXA) such that changes as littleas 1% can be quantified. We have utilized DEXA to evaluate changes inbone mineral density due to estrogen deficiency following ovariectomy(surgical removal of ovaries) and treatment with vehicle, estradiol(E2), keoxifen (raloxifen), or other estrogen agonists. The purpose ofthese studies is to evaluate the ability of the compounds of thisinvention to prevent estrogen deficiency bone loss as measured by DEXA.

Female (S-D) rats 4-6 months of age undergo bilateral ovariectomy orsham surgery and allowed to recover from anesthesia. Rats are treated bys.c. injection or oral gavage with various doses (10-1000, μg/kg/day,for example) of compound of Formula I daily for 28 days. All compoundsare weighed and dissolved in 10% ethanol in sterile saline. After 28days the rats are killed and femora removed and defleshed. The femoralare positioned on a Hologic QDR1000W (Hologic, Inc. Waltham, Mass.) andbone mineral density is determined in the distal portion of the femur ata site from 1 cm to 2 cm from the distal end of the femur using the highresolution software supplied by Hologic. Bone mineral density isdetermined by dividing the bone mineral content by the bone area of thedistal femur. Each group contains at least 6 animals. Mean bone mineraldensity is obtained for each animal and statistical differences (p<0.05)from the vehicle-treated ovariectomy and sham-operated group weredetermined by t test.

In Vitro Estrogen Receptor Binding Assay

An in vitro estrogen receptor binding assay, which measures the abilityof the compounds of the present invention to displace [3H]-estradiolfrom human estrogen receptor obtained by recombinant methods in yeast,is used to determine the estrogen receptor binding affinity of thecompounds of this invention. The materials used in this assay are: (1)Assay buffer, TD-0.3 (containing 10 nM Tris, pH 7.6, 0.3 M potassiumchloride and 5 mM DTT, pH 7.6); (2) The radioligand used is[3H]-estradiol obtained from New England Nuclear; (3) the cold ligandused is estradiol obtained from Sigma (4) recombinant human estrogenreceptor, hER.

A solution of the compound being tested is prepared in TD-0.3 with 4%DMSO and 16% ethanol. The tritiated estradiol is dissolved in TD-0.3such that the final concentration in the assay was 5 nM. The hER is alsodiluted with TD-0.3 such that 4-10 μg of total protein was in each assaywell. Using microtitre plates, each incubate received 50 ul of coldestradiol (nonspecific binding) or the compound solution, 20 uL of thetritiated estradiol and 30 ul of hER solutions. Each plate contains intriplicate total binding and varying concentrations of the compound. Theplates are incubated overnight at 4° C. The binding reaction is thenterminated by the addition and mixing of 100 mL of 3% hydroxylapatite in10 mM tris, pH 7.6 and incubation for 15 minutes at 4° C. The mixturesis centrifuged and the pellet washed four times with 1% Triton-X100 in10 mM Tris, pH 7.6. The hydroxylapatite pellets are suspended inEcoscint A and radioactivity is assessed using beta scintigraphy. Themean of all triplicate data points (counts per minute, cpm's) isdetermined. Specific binding is calculated by subtracting nonspecificcpm's (defined as counts that remain following separation of reactionmixture containing recombinant receptor, radioligand, and excessunlabeled ligand) from total bound cpm's (defined as counts that remainfollowing the separation of reaction mixture containing only recombinantreceptor, radioligand). Compound potency is determined by means of IC50determinations (the concentration of a compound needed to inhibition 50%of the of the total specific tritiated estradiol bound). Specificbinding in the presence of varying concentrations of compound isdetermined and calculated as percent specific binding of total specificradioligand bound. Data are plotted as percent inhibition by compound(linear scale) versus compound concentration (log scale).

Effect on Total Cholesterol Levels

The effect of the compounds of the present invention on plasma levels oftotal cholesterol is measured in the following way. Blood samples arecollected via cardiac puncture from anesthetized female (S-D) rats 4-6months of age that are bilaterally ovariectomized and treated with thecompound (10-1000 μg/kg/day, for example, sc or orally for 28 days orwith vehicle for the same time), or sham operated. The blood is placedin a tube containing 30 μL of 5% EDTA (10 μL EDTA/1 mL of blood). Aftercentrifugation at 2500 rpm for 10 minutes at 20° C. the plasma isremoved and stored at −20° C. unit assay. The total cholesterol isassayed using a standard enzymatic determination kit from SigmaDiagnostics (Procedure No. 352).

Effect on Obesity

Sprague-Dawley female rats at 10 months of age, weighing approximately450 grams, are sham-operated (sham) or ovariectomized (OVX) and treatedorally with vehicle, 17α ethynyl estradiol at 30 μg/kg/day or a compoundof formula I at 10-1000 μg/kg/day for 8 weeks. There are 6 to 7 rats ineach sub group. On the last day of the study, body composition of allrats is determined using dual energy x-ray abosorptiometry (HologicQDR-1000/W) equipped with whole body scan software which shows theproportions of fat body mass and lean body mass.

A decrease in fat body mass indicates that the estrogen agonists offormula I are useful in preventing and treating obesity.

Pharmaceutical chemists will easily recognize that physiologicallyactive compounds which have accessible hydroxy groups are frequentlyadministered in the form of pharmaceutically acceptable esters. Theliterature concerning such compounds, such as estradiol, provides agreat number of instances of such esters. The compounds of thisinvention are no exception in this respect, and can be effectivelyadministered as an ester, formed on the hydroxy groups, just as oneskilled in pharmaceutical chemistry would expect. While the mechanismhas not yet been investigated, it is believed that esters aremetabolically cleaved in the body, and that the actual drug, which suchform is administered, is the hydroxy compound itself. It is possible, ashas long been known in pharmaceutical chemistry, to adjust the rate orduration of action of the compound by appropriate choices of estergroups.

Certain ester groups are preferred as constituents of the compounds ofthis invention. The compounds of formula I may contain ester groups atvarious portions as defined herein above, where these groups arerepresented as —COOR⁹. R⁹ is C₁-C₁₄ alkyl, C₁-C₃ chloroalkyl, C₁-C₃fluoroalkyl, C₅-C₇ cycloalkyl, C₁-C₄ alkoxy, phenyl or phenyl mono- ordisubstituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, nitro, chloro,fluoro or tri(chloro or fluoro)methyl.

The pharmaceutically acceptable acid addition salts of the compounds ofthis invention may be formed of the compound itself, or of any of itsesters, and include the pharmaceutically acceptable salts which areoften used in pharmaceutical chemistry. For example, salts may be formedwith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfonic acids including such agents asnaphthalenesulfonic, methanesulfonic and toluenesulfonic acids, sulfuricacid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuric acid,metaphosphoric acid, succinic acid, formic acid, phthalic acid, lacticacid and the like, most preferable with hydrochloric acid, citric acid,benzoic acid, maleic acid, acetic acid and propionic acid. It is usuallypreferred to administer a compound of this invention in the form of anacid addition salt, as it is customary in the administration ofpharmaceuticals bearing a basic group such as the pyrrolidino ring.

The compounds of this invention, as discussed above, are very oftenadministered in the form of acid addition salts. The salts areconveniently formed, as is usual in organic chemistry, by reacting thecompound of this invention with a suitable acid, such as have beendescribed above. The salts are quickly formed in high yields at moderatetemperatures, and often are prepared by merely isolating the compoundfrom a suitable acidic wash as the final step of the synthesis. Thesalt-forming acid is dissolved in an appropriate organic solvent, oraqueous organic solvent, such as an alkanol, ketone or ester. On theother hand, if the compound of this invention is desired in the freebase form, it is isolated from a basic final wash step, according to theusual practice. A preferred technique for preparing hydrochlorides is todissolve the free base in a suitable solvent and dry the solutionthoroughly, as over molecular sieves, before bubbling hydrogen chloridegas through it.

The dose of a compound of this invention to be administered to a humanis rather widely variable and subject to the judgement of the attendingphysician. It should be noted that it may be necessary to adjust thedose of a compound when it is administered in the form of a salt, suchas a laureate, the salt forming moiety of which has an appreciablemolecular weight. The general range of effective administration rates ofthe compounds is from about 0.05 mg/day to about 50 mg/day. A preferredrate range is from about 0.25 mg/day to 25 mg/day. Of course, it isoften practical to administer the daily dose of compound in portions, atvarious hours of the day. However, in any given case, the amount ofcompound administered will depend on such factors as the solubility ofthe active component, the formulation used and the route ofadministration.

The route of administration of the compounds of this invention is notcritical. The compounds are known to be absorbed from the alimentarytract, and so it is usually preferred to administer a compound orallyfor reasons of convenience. However, the compounds may equallyeffectively be administered percutaneously, or as suppositories forabsorption by the rectum, if desired in a given instance.

The compounds of this invention are usually administered aspharmaceutical compositions which are important and novel embodiments ofthe invention because of the presence of the compounds. All of the usualtypes of compositions may be used, including tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions. Compositions are formulated to contain a daily dose, or aconvenient fraction of daily dose, in a dosage unit, which may be asingle tablet or capsule or convenient volume of a liquid.

Any of the compounds may be readily formulated as tablets, capsules andthe like; it is preferable to prepare solutions from water-solublesalts, such as the hydrochloride salt.

In general, all of the compositions are prepared according to methodsusual in pharmaceutical chemistry.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used as well assodium lauryl sulfate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established in the art.

When it is desired to administer a compound as a suppository, thetypical bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the compounds may be delayed or prolonged by properformulation. For example, a slowly soluble pellet of the compound may beprepared and incorporated in a tablet or capsule. The technique may beimproved by making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules maybe coated with a film which resists dissolution for a predictable periodof time. Even the parenteral preparations may be made long-acting, bydissolving or suspending the compound in oily or emulsified vehicleswhich allow it to disperse only slowly in the serum.

The following examples will serve to illustrate, but do not limit, theinvention which is defined by the claims.

EXAMPLES Example 1Cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl-5,6,7,8-tetrahydronaphthalen-2-olStep Acis-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine.

A solution of 1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride)(1.0 g, 2.16 mmol) in 20 mL of absolute ethanol containing 1.0 g ofpalladium hydroxide on carbon was hydrogenated at 50 psi at 20° C. for19 hr. Filtration and evaporation provided 863 mg (93%) ofcis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxylethyl}pyrrolidine:¹H-NMR (CDCl₃): δ3.50-3.80 (m, 3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H),6.80-7.00 (m, 3H); MS 428 (P⁺+1).

Step B

To a solution of 400 mg (0.94 mmol) of the product from Step A in 25 mlof methylene chloride at 0° C. was added, dropwise with stirring, 4.7 ml(4.7 mmol) of a 1.0 M solution of boron tribromide in methylenechloride. After 3 hours at room temperature, the reaction was pouredinto 100 ml of rapidly stirring satd aq sodium bicarbonate. The organiclayer was separated, dried over sodium sulfate, filtered, andconcentrated to afford 287 mg (74% yield) of the title substance as thefree base. ¹H-NMR (CDCl₃): δ3.35 (dd, 1H), 4.00 (t, 2H), 4.21 (d, 1H),6.35 (ABq, 4H). The corresponding hydrochloride salt was prepared bytreating a solution of the base with excess 4N HCl in dioxane, followedby evaporation to dryness and ether trituration (MS: 415[P⁺+1]).

An alternative method useful for the preparation of Example 1 isdescribed below.

Step A1-{2-]4-(6-Methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]lethyl}pyrrolidine

A mixture of anhydrous CeCl₃ (138 g, 560 mmol) and THF (500 mL) wasvigorously stirred for 2 h. In a separate flask, a solution of1-[2-(4-bromophenoxy)ethyl]pyrrolidine (100 g, 370 mmol) in THF (1000mL) was cooled to −78° C. and n-BuLi (2.6 M in hexanes, 169 mL, 440mmol) was slowly added over 20 min. After 15 min, the solution was addedto the CeCl₃ slurry cooled at −78° C. via cannula and the reaction wasstirred for 2 h at −78° C. A solution of 6-methoxy-1-tetralone (65.2 g,370 mmol) in THF (1000 mL) at −78° C. was added to the arylceriumreagent via cannula. The reaction was allowed to warm slowly to roomtemperature and was stirred for a total of 16 h. The mixture wasfiltered through a pad of celite. The filtrate was concentrated in vacuoand 3 N HCl (500 mL) and Et₂O (500 mL) were added. After stirring for 15min, the layers were separated. The aqueous layer was further washedwith Et₂O (2×). The combined organic layers were dried (MgSO₄),filtered, and concentrated to provide 6-methoxy-1-tetralone (22 g). Theaqueous layer was basified to pH 12 with 5 N NaOH and 15% aqueous(NH₄)₂CO₃ (1000 mL) was added. The aqueous mixture was extracted withCH₂Cl₂ (2×). The organic solution was dried (MgSO₄), filtered, andconcentrated to provide a brown oil. Impurities were distilled off(110-140° C. @ 0.2 mmHg) to yield the product (74 g, 57%). ¹H NMR (250MHz, CDCl₃): δ7.27 (d, J=8.7Hz, 2H), 6.92-6.99 (m, 3H), 6.78 (d, J=2.6Hz, 1H), 6.65 (dd, J=8.6, 2.6Hz, 1H), 5.92 (t,J=4.7 Hz, 1H), 4.15 (t,J=6.0 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.0 Hz, 2H), 2.81 (t, J=7.6 Hz,2H), 2.66 (m, 2H), 2.37 (m, 2H), 1.84 (m, 4H).

Step B1-{2-[4-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine

Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was addedportionwise to a solution of1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine(23 g, 72 mmol) in THF (700 mL). The reaction was stirred for 60 h. Theprecipitate was filtered through a Celite pad with the aid of THF. Theoff-white solid was dissolved in CH₂Cl₂ and MeOH and was filtered awayfrom the Celite. The organic solution was washed with 0.5 N aq HClfollowed by satd NaHCO₃ (aq). The organic solution was dried (MgSO₄),filtered, and concentrated to provide a brown solid (21.5 g, 83%). ¹HNMR (250 MHz, CDCl₃): δ7.14 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H),6.71 (d, J=2.2 Hz, 1H), 6.55 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 3.77 (s,3H), 2.96 (m, 4H), 2.66 (m, 4 H), 1.85 (m, 4H).

Step C1-{2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxylethyl]pyrrolidinehydrochloride (Nafoxidene hydrochloride)

To a mixture of1-{2-[4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine(19 g, 44 mmol), phenylboronic acid (7.0 g, 57 mmol), andtetrakis(triphenylphosphonium)palladium (1.75 g, 1.51 mmol) in THF (300mL) was added Na₂CO₃ (13 g, 123 mmol) in H₂O (100 mL). The reaction washeated at reflux for 18 h. The layers were separated and the organiclayer was washed with H₂0 followed by brine. The organic solution wasdried (MgSO₄), filtered, and concentrated to yield 17.96 g of a brownsolid. The residue was dissolved in a 1:1 mixture of CH₂Cl₂ and EtOAc(250 mL) and 1 N HCl in Et₂O (100 mL) was added. After stirring for 2 h,product was allowed to crystallize from solution and 11 g of materialwas collected by filtration. Concentration of the mother liquor to halfits volume provided an additional 7.3 g of product.

Step Dcis-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine

1-{2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidinehydrochloride (nafoxidene hydrochloride) (75 g, 162 mmol) was dissolvedin 1000 mL of EtOH and 300 mL of MeOH. Dry Pd(OH)₂ on carbon was addedand the mixture was hydrogenated on a Parr shaker at 50° C. and 50 psifor 68 h. The catalyst was filtered off with the aid of celite and thesolvents were removed in vacuo. The resulting white solid was dissolvedin CH₂Cl₂ and the solution was washed with satd NaHCO₃ (aq). The organicsolution was dried (MgSO₄), filtered, and concentrated to yield anoff-white solid (62.6 g, 90%).

Step Ecis-6-Phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol

A mixture ofcis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine(12 g, 28 mmol), acetic acid (75 mL), and 48% HBr (75 mL) was heated at100° C. for 15 h. The solution was cooled and the resulting whiteprecipitate was collected by filtration. The hydrobromide salt (9.6 g,69%) was dissolved in CHCl₃MeOH and was stirred with satd NaHCO₃ (aq).The layers were separated and the aqueous layer was further extractedwith CHCl3/MeOH. The combined organic layers were dried (MgSO₄),filtered, and concentrated to yield product as an off-white foam. ¹H NMR(250 MHz, CDCl₃): δ7.04 (m, 3H), 6.74 (m, 2H), 6.63 (d, J=8.3 Hz, 2H),6.50 (m, 3H), 6.28 (d, J=8.6 Hz, 2H), 4.14 (d, J =4.9 Hz, 1H), 3.94 (t,J=5.3 Hz, 2H), 3.24 (dd, J=12.5, 4.1 Hz, 1H), 2.95 (m, 4H), 2.78 (m,4H), 2.14 (m, 1H), 1.88 (m, 4H), 1.68 (m, 1H).

Example 2Trans6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-olStep A

To a solution ofcis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine(500 mg, 1.17 mmol) in 10 ml of dimethyl sulfoxide at 10° C. was addedslowly 4.7 ml (11.7 mmol) of 2.5 M n-butyl lithium in hexane. Thereaction was allowed to warm to 20° C. and was stirred for 19 hrs. Afteraddition of water and extraction with ether, the organic layers werecombined, dried over magnesium sulfate, filtered and concentrated todryness to yield 363 mg (73%) of the trans-6-methoxydihydronaphthalene.¹H-NMR (CDCl₃): δ3.45 (m, 2H), 3.82, (s, 3H), 4.06 (d, 1H), 4.45 (m,2H), 6.80 (d, 2H).

Step B

Using the boron tribromide deprotection procedure described in Example 1Step B, 363 mg (0.85 mmol) of the product of Step A was converted to 240mg (68%) of the title compound. ¹H-NMR (CDCl₃): δ4.02 (d, 1H), 4.45 (m,2H), 7.00 (d, 2H). The corresponding hydrochloride salt was prepared asdescribed in Step B of Example 1 (MS 414 P⁺+1).

Example 31-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride Step A 3-Methoxyphenylacet-4′-methoxyanilide

A solution of 20.0 g (0.120 mole) of 3-methoxyphenylacetic acid and 40ml (65.3 g, 0.549 mole) of thionyl chloride in 100 ml of benzene washeated at reflux for 2 hours and evaporated to dryness to afford thecorresponding acid chloride (assume 0.120 mole). The acid chloride wasslurried in 50 ml of ether and added to a mixture of 4-methoxyaniline in100 ml of ether at 0° C. After stirring at 200° C. overnight, the slurrywas filtered to afford a solid which was washed with water, 5.5% aq HCl,water, and ether. Subsequent drying over P₂O₅ in vacuo for 4 hr. yielded19.7 g (60%) of the title substance as a white solid. ¹H-NMR (CDCl₃):δ3.70 (s, 2H), 3.77 (s, 3H), 3.81 (s, 3H).

Step B N-(4-Methoxyphenyl)-2′-(3″-methoxy Phenethylamine) hydrochloride

A slurry of 19.6 g (0.072 mol) of the product of Step A and 6.04 g(0.159 mol) of lithium aluminum hydride in 130 ml of ether and 75 ml ofdioxane was heated at 35° C. for 48 hrs. Excess sodium sulfitedecahydrate was added and the mixture was filtered and washed with 5% aqHCl. The organic layer was dried over anhydrous magnesium sulfate andconcentrated to yield 10.84 g of the title substance as the HCl salt(51%). ¹H-NMR (CDCl₃): δ3.15 (m, 2H), 3.42 (m, 2H), 3.71 (s, 3H), 3.74(s, 3H).

Step C N-2-(3′-Methoxphenethyl)-4″-benzyloxybenz-4″′-methoxyanilide

To a slurry of 4.83 g (0.164 mol) of the product of Step B and 2.12 g(0.0164 mol) of diisopropylethylamine in 50 ml of ether was added 0.013mol of 4-benzyloxybenzoyl chloride [prepared from 3.00 g (0.013 mol) ofthe corresponding benzoic acid and 7.13 g (0.059 mol) of thionylchloride in 35 ml of benzene] in 50 ml of ether at 20° C. and thereaction was stirred overnight. After decantation from a precipitate,the ether solution was washed with 5% aq HCl, water, brine, dried overmagnesium sulfate, filtered and evaporated to dryness to yield 5.58 g ofthe title substance (73%). ¹H-NMR (CDCl₃): δ3.00 (m, 2H), 3.75 (m, 9H),4.05 (m, 2H).

Step D 1-(4′-Benzyloxyphenyl)-2-(4″-methoxyphenyl)-6-methoxy-3,4-dihydroisoquinolinium chloride

A solution of 1.04 g (2.22 mmol) of the product of step C in 5 ml ofphosphorous oxychloride was heated at 100° C. for 2.5 hrs. The reactionwas evaporated to dryness and partitioned between ethyl acetate/water.The ethyl acetate layer was dried over anhydrous magnesium sulfate andconcentrated to yield 1.03 g of the title substance as an oil (96%).¹H-NMR (CDCl₃): δ3.46 (t, 2H), 3.80 (s, 3H), 4.00 (s, 3H), 4.55 (t, 2H).

Step E 1-(4′-Benzyloxyphenyl)-2-(4″-methoxyphenyl)-6-methoxy-12,3,4-tetrahydroisoquinoline

To 1.00 g of the product of Step D (2.07 mmol) in 10 ml of methanol wasadded 200 mg (5.28 mmol) of sodium borohydride. After stirring 19 hrs at25° C., the precipitate was collected and dried in vacuo to yield 611 mg(66%) of the title substance as a foam. ¹H-NMR (CDCl₃): δ2.95 (m, 2H),3.50 (m, 2H), 3.71 (s, 3H), 3.78 (s, 3H), 5.09 (s,1H).

Step F1-(4′-Hydroxyphenyl)-2-(4″-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of 611 mg (1.35 mmol) of the product of Step E in 6 ml ofconc. aq HCl and 6 ml of dioxane was heated at 90° C. for 5 hrs. Thedioxane was removed in vacuo and the aqueous layer diluted with water.The title compound was isolated (155 mg, 29%) as the precipitatedhydrochloride salt. ¹H-NMR (CDCl₃): δ3.72 (s, 3H), 3.76 (s, 3H), 5.94(s, 1H).

Step G1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

To a slurry of 152 mg (0.382 mmol) of the product of Step F in 5 ml ofdioxane and 1 ml of DMF was added 152.8 mg (3.82 mmol) of 60% sodiumhydride mineral oil dispersion. After stirring at 45° C. for 0.5 hr., 65mg (0.382 mmol) of 2-chloroethylpyrrolidine hydrochloride was addedslowly portionwise and was stirred for 3 hr at 45° C. After addition ofwater, the reaction was extracted with ethyl acetate. The ethyl acetatelayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated to yield 203 mg of crude product which was chromatographedon silica gel with chloroform/methanol (99:1) to afford 78 mg (45%) ofthe title substance. ¹H-NMR (CDCl₃): δ2.85 (m, 2H), 3.72 (s, 3H), 3.79(s, 3H), 4.00 (t, 2H), 5.50 (s, 1H).

Step H1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetrahydroiosquinolinehydrochloride

To a solution of 75 mg (0.164 mmol) of the product of Step G in 5 ml ofmethylene chloride at 0° C. was added dropwise 0.82 ml (0.82 mmol) of1.0 M boron tribromide in methylene chloride. After stirring at 0° C.for 0.5 hr, the reaction was allowed to process at 20° C. for 2 hrs. Thereaction was poured into ice cold satd aq sodium bicarbonate. Thesupernatant was filtered off from the gum which was dissolved inmethanol, dried over magnesium sulfate, filtered and evaporated todryness to yield 53 mg (75%) of the title substance as a foam. ¹H-NMR(CD₃OD): δ4.02 (m, 2H), 5.50 (s, 1H), 6.50-7.00 (m, 11H). Thehydrochloride salt prepared in the usual manner was a white solid: MS431 (P⁺+1).

Example 41-(6′-Pyrrolidinoethoxy-3′-pyridyl)-2-(4″-hydroxyphenyl)-6-hydroxy-12,3,4-tetrahydroisoquinoline hydrochloride Step A1-(6′-Chloro-3′-pyridyl)-2-(4″-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

Using the procedures described for Example 3 described in step C,substituting 6-chloronicotinoyl chloride for 4-benzyloxybenzoylchloride, the title compound was obtained.

Step B1-(6′-Pyrrolidinoethoxy-3′-pyridyl)-2-(4″-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

The product of Step A (500 mg, 1.31 mmol) was slurried in 10 ml oftoluene and treated with 364 mg (5.52 mmol) of potassium hydroxide, 346mg (1.31 mmol) of 18-crown-6, and 318 mg (2.76 mmol) of1-(2-hydroxyethyl)pyrrolidine. After heating at 80° C. for 18 hr, thereaction was cooled, diluted with water, and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated to dryness to afford575 mg of a foam Chromatography on silica gel using 97.5%chloroform/methanol (9:1) and 2.5% conc. NH₄OH yielded 127 mg (21 %) ofthe title substance. ¹H-NMR (CDCl₃): δ2.50 (m, 4H), 2.90 (m, 4H), 3.42(m, 2H), 3.72 (s, 3H), 3.79 (s, 3H), 4.39 (t, 2H), 5.05 (s, 1H).

Step C

The product of Step B was deprotected according to the procedure ofExample 1 and converted to the hydrochloride salt in the usual manner toafford the title substance. ¹H-NMR (CDCl₃): δ2.55 (m, 2H), 5.45 (s, 1H);MS (P⁺+1) 432.

Example 51-(4-Azabicycloheptanoethoxyphenyl)-2-(4″-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

Using the procedures of Example 3, substituting in Step C,4-(2′-azabicyclo[2.2.1 ]heptanoethoxy)benzoic acid for 4-benzyloxybenzoic acid, followed by the employment of Steps D, E, and H, the titlesubstance was obtained as a white solid. ¹H-NMR (CDCl₃): δ2.95 (m, 3H),3.90 (s, 1H), 4.15 (t, 3H), 5.42 (s, 1H); MS 457 (P⁺+1).

Example 6(−)-cis-6-Phenyl-5-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-olStep A 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine

A solution of 2,5-dibromopyridine (15.0 g, 63.3 mmol), powdered KOH(6.39 g, 114 mmol), 1-(2-hydroxyethyl)pyrrolidine (14.58 g, 126.6 mmol),and 18-crown-6 (300 mg, 1.14 mmol) in dry toluene (100 mL) was heated to70° C for 1 h. The solution was cooled to room temperature and water andEtOAc were added. The organic layer was washed with water and brine. Thesolution was dried (MgSO₄), filtered, and concentrated in vacuo. Shortpath distillation (153° C. @ 0.1 mmHg) provided the title compound as acolorless oil which solidified upon cooling (14.9 g, 87%). ¹H NMR (250MHz, CDCl₃): δ8.15 (d, J=2.4 Hz, 1H), 7.65 (dd, J=2.4, 8.4 Hz, 1H), 6.67(d, J =8.4 Hz, 1H), 4.38 (t, J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.62(m, 4H), 1.82 (m, 4H).

Step B6-Methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine (7.0 g, 26mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in hexanes,12.4 mL, 31.0 mmol) dropwise. After 30 min, 6-methoxy-1-tetralone (4.55g, 25.8 mmol) in dry THF was added. After stirring for 15 min at −78°C., the reaction was allowed to warm to room temperature. After 30 min,the reaction was poured into aq NaHCO3 (satd). The aqueous layer wasextracted with EtOAc (2×). The combined organic solutions were dried(MgSO₄), filtered, and concentrated. Flash chromatography (CHCl₃:MeOH,95:5) provided the alcohol (4.23 g, 44%) as a white solid. ¹H NMR (250MHz, CDCl₃): δ8.07 (d, J=2.5Hz, 1H), 7.49 (dd, J=2.5, 8.7 Hz, 1H), 7.00(d, J=8.5 Hz, 1H), 6.73 (m, 3H), 4.45 (t, J=5.7 Hz, 2H), 3.79 (s, 3H),2.92 (t, J=5.7 Hz, 2H), 2.76 (m, 2H), 2.67 (m, 4H), 2.11 (s, 1H), 2.08(m, 3H), 1.82 (m, 5H).

Step C5-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine

Pyridinium bromide perbromide (3.5 g, 12.2 mmol) was added to a solutionof6-methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-1-ol(3.3 g, 8.9 mmol) in CH₂Cl₂ (50 mL). The reaction was stirred for 18 hand aqueous NaHCO₃ (satd) was added. The aqueous layer was extractedwith CH₂Cl₂ and the combined organic solution was washed with water andbrine. The organic solution was dried (MgSO₄), filtered, andconcentrated. Flash chromatography (CHCl₃:MeOH, 95:5) provided thedesired vinyl bromide (2.65 g, 70%). ¹H NMR (250 MHz, CDCl₃): δ8.0 (d,J=2.4 Hz, 1H), 7.41 (dd, J=2.4, 8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H),6.69 (m, 1H), 6.55 (m, 2H), 4.92 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 2.94(m, 6H), 2.64 (m, 4 H), 1.82 (m, 4H).

Step D5-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine

Phenyllithium (1.8 M in cyclohexane/ether, 3.8 mL, 7.0 mmol) was addedslowly to zinc chloride (0.5 M in THF, 14 mL, 7.0 mmol) at 0° C. Afterstirring for 15 min,5-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine(1.0 g, 2.3 mmol) in dry THF (20 mL) was added followed by Pd(PPh₃)₄(200 mg, 0.173 mmol). The reaction was warmed to room temperature andwas heated at reflux for 4 h. The reaction was poured into aqueous NH₄Clsolution (satd). The aqueous layer was washed with CHCl₃ (2×) and thecombined organic solutions were washed with water followed by brine. Theorganic solution was dried (MgSO₄), filtered, and concentrated in vacuo.Flash chromatography (CHCl₃:MeOH, 95:5) provided the title compound (680mg, 68%). ¹H NMR (250 MHz, CDCl₃): δ7.78 (d, J=2.1 Hz, 1H), 7.27 (m,1H), 7.07 (m, 5H), 6.68 (m, 4H), 4.40 (t, J=5.8 Hz, 2H), 3.80 (s, 3H),2.88 (m, 6H), 2.71 (m, 4 H), 1.81 (m, 4H).

Step Ecis-5-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine

Pd(OH)₂ (20%, 77 mg) was flame dried under vacuum and was added to asolution of5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine(286.4 mg, 0.6714 mmol) in acetic acid (50 mL). The mixture washydrogenated on a Parr shaker at 50 psi and at 50° C. for 16 h. Thecatalyst was filtered off with the aid of celite and the acetic acid wasremoved in vacuo. ¹H NMR indicated that the reaction was incomplete andthe residue was resubjected to the reaction conditions (50 psi and 60°C.) for an additional 6 h. The catalyst was removed via filtrationthrough celite and the solvent was removed in vacuo. Radialchromatography (solvent gradient, CH₂Cl₂ to 10% MeOH in CH₂Cl₂) providedthe desired material (207 mg, 72%). ¹H NMR (250 MHz, CDCl₃): δ7.19 (m,4H), 6.84 (m, 3H), 6.75 (d, J=2.4 Hz, 1H), 6.68 (dd, J=2.4, 8.4 Hz, 1H),6.59 (dd, J=2.4, 8.4 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.35 (t, J=5.7 Hz,2H), 4.21 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 3.38 (m, 1H), 3.06 (m, 2H),2.90 (t, J=5.7 Hz, 2H), 2.69 (m, 4H), 2.11 (m, 2H), 1.84 (m, 4H).

Step Fcis-6-Phenyl-5-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-ol

To a solution ofcis5-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine(69.6 mg, 0.162 mmol) in dry CH₂Cl₂ (3 mL) at 0° C. was added AlCl₃ (110mg, 0.825 mmol) followed by excess EtSH (400 μL). After 0.5 h, thereaction was warmed to room temperature and additional AlCl₃ (130 mg)was added. After 0.5 h, aqueous NaHCO₃ (satd) was carefully added andthe aqueous layer was extracted with CH₂Cl₂/MeOH (3×). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated. Radialchromatography (solvent gradient, CH₂Cl₂ to 15% MeOH in CH₂Cl₂) providedthe deprotected material (64.6 mg, 96%) as an off-white solid. ¹H NMR(250 MHz, CDCl₃): δ7.18 (m, 3H), 6.96 (d, J=2.4 Hz, 1H), 6.82 (m, 2H),6.70 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.62 (dd, J=2.4, 8.5 Hz,1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H), 5.80 (d, J=8.5 Hz, 1H), 4.45 (m, 2H),4.18 (d, J=4.8 Hz, 1H), 3.40 (m, 1H), 3.04 (m, 3H), 2.75 (m, 6H), 2.11(m, 1H), 1.88 (m, 4H). The two enantiomers were isolated bychromatography on a 5 cm id×5 cm Chiracel OD column using 5% ethanol/95%heptane with 0.05% diethylamine. Enantiomer 1: R_(t)=17.96 min,[α]_(d)=242 (c=1, MeOH); Enantiomer 2: R_(t)=25.21 min, [α]_(d)=−295(c=1, MeOH).

Example 7Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydronaphthalen-2-olStep A

1 g of 1-[4′-piperidino ethoxy phenyl]-2-[4″-fluorophenyl]-6-methoxy-3,4-dihydronaphthalene (which can be made as inExample 1 but replacing phenylboronic acid in Step C with4-fluorophenylboronic acid) in 35 ml acetic acid was added palladiumhydroxide on carbon (20%, 1 g)(flame dried in vacuo). The mixture washydrogenated on a Parr shaker at 50° C. and 50 psi for 4 hours.Filtration through Celite and concentration yielded 1.2 g of crudereaction product which was used without further purification in the nextstep.

¹H-NMR (250 MHz, CDCl₃): δ1.9 (m), 3.1 (m), 3.25 (m), 3.8 (s, 3H), 4.2(d, 1H), 4.25 (bd), 6.35 (d, 2H), 6.5 (d, 2H), 6.65 (m), 6.75 (m),6.8-6.88 (m).

m/z 460 (M+1)

Step B

A solution of cis-1-[4-piperidinoethoxy phenyl]-2-[4″-fluorophenyl]-6-methoxy-1,2,3,4 -tetrahydronaphthalene-1-yl]phenoxy}-ethyl)-piperidine (540 mg, 1.17 mmol) inanhydrous CH₂Cl₂ was cooled to 0° C. followed by the addition of BBr₃[5.8 mL (1 M solution in CH₂Cl₂), 5.88 mmol] dropwise. The reaction wasallowed to warm to room temperature and stirred for another hour. Afterthe reaction was complete, the reaction was cooled back to 0° C. andaqueous NaHCO₃ was carefully added. The aqueous layer was extracted withCH₂Cl₂ (3×). The organic layer was dried over MgSO₄, filtered andconcentrated. The crude product was radially chromatographed (solvent4:1 ether /hexane, 1% triethylamine) to provide the deprotected product.The HCl salt product was form with 1 M HCl/Ether solution followed bytrituration with EtOAc/THF to provide 126 mg of product. ¹H NMR (250MHz,CDCl₃): δ6.80 (m,4H), 6.63 (m, 4H), 6.50 (dd, 1H), 6.40 (d, 2H), 4.22(dd, 3H), 3.72 (m, 2H), 3,48 (dd, 2H), 3.0 (bm, 2H), 1.83 (m, 9H). m/z446 (M+1)

Example 8(−)Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

The racemic compound of Example 1 (3 g) was subjected to enantiomericseparation on a 5 cm ×5 cm Chiralcell OD column employing 99.95% (5%EtOH/95% heptane)/0.05% diethylamine as the element to afford 1 g of afast eluting (+) enantiomer and 1 g of a slow (−) eluting enantiomer,both of which possessed identical NMR, MS and TLC behavior as theracemate. Alternatively, a crystallization procedure using R-binapphosphoric acid can be employed to effect resolution. In 20 ml ofmethanol and 20 ml of methylene chloride was added 7.6 g (0.0184 mol) ofthe product of Example 1 and 6.4 g (0.0184 mol) of R-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate. After solution was complete,evaporation of solvent followed by trituration with ether afforded 1 4.2g of racemic salt. This solid was slurried in 500 ml of dioxane and 25ml of methanol and the resulting mixture was heated until the initialsolid dissolved. On standing for 1 hour, a white precipitate formed (6.8g) which was collected and which HPLC (using the conditions above)indicated to be approximately 73% enantiomerically pure. This materialwas slurried in 250 ml of absolute ethanol and heated until solution wasachieved, at which time the solution was allowed to stand at roomtemperature overnight. The collected crystals were washed with coldethanol followed by ether to afford 3.1 g of 98% enantiomerically puresalt; a second crop of 588 mg was also obtained. Partitioning between 1:2 methanol/methylene chloride and 1% aqueous sodium hydroxide affordedthe corresponding free base which was converted to the hydrochloridesalt (HCl in dioxane). Recrystallization from acetonitrile/methylenechloride afforded the levorotatory preferred enantiomer hydrochloridecorresponding to Example 1. [α_(D)−330.6 (c=0.05,CH₂Cl₂]; mp 260-263° C.

Example 9Cis-6-(4′-hydroxyphenyl)-5-[4-(2-Piperidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol

Following the procedures described for the preparation of Example 1, thetitle compound was obtained. ¹H NMR (CDCl₃): δ3.12 (m, 1H); 3.90 (m,2H); 4.15 (d, 1H); 6.15-6.72 (m, 11H); FAB MS (M+1) 430.

Example 101-(4′-Piperidinoethoxyphyenyl)-2-(4″-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

Using the procedure of Example 3 described in step G, substitutingN-2-chloroethylpiperidine hydrochloride for N-2-chloroethylpyrrolidinehydrochloride, the title compound was obtained. ¹H NMR (CDCl₃): δ2.65(m, 2H); 2.75 (m, 2H); 5.45 (s, 1); 6.50-7.00 (m, 11H); FAB MS(M+1) 445.

Example 111-(4′-Pyrrolidinoethoxoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

The title compound was obtained using the procedure of Example 3described in step A, substituting 4-fluoroaniline for 4-methoxyaniline.¹H NMR (CDCl₃): δ2.12 (m, 2H); 3.65 (m, 2H); 4.45 (m, 2H); 6.10 (s, 1H);7.5 (m, 2H); FAB MS(M+1) 433.

Example 121-(4′-Pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

The title compound was prepared using the procedure of Example 3described in step A, substituting aniline for 4-methoxyaniline. ¹H NMR(CDCl₃): δ1.70 (m, 4H); 2.70 (m, 2H); 4.00 (m, 2H); 5.70 (s, 1H);6.60-7.25 (m, 12H); FAB MS(M+1) 415.

What is claimed is:
 1. The compound1-{2-[4-(6-Methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine.2. The compound1-{2-[4-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine.3. The compoundcis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl}-5,6,7,8-tetrahydronaphthalen-2-ol,hydrobromide salt.